Lethal and sublethal genes

Genetic patterns

Most lethal alleles are recessive because a normal heterozygote can transmit them. When two heterozygotes mate, the lethal homozygote may disappear before observation, changing the surviving Mendelian ratio from 3:1 to 2:1. Tay–Sachs disease is an autosomal-recessive example historically lethal in early childhood without effective supportive care.

Some alleles are dominant for a visible trait but homozygous lethal. In achondroplasia, one altered FGFR3 allele causes short-limbed dwarfism, while two altered copies usually cause lethal skeletal dysplasia. Two affected heterozygous parents therefore face a 1/4 homozygous-lethal conception risk.

Dominant lethals can persist when expression follows reproduction. Huntington disease, caused by a HTT CAG expansion, reduces survival but often has adult onset; it is better described as a late-acting deleterious dominant than as an invariably pre-reproductive lethal.

Sublethal effects form a continuum. Untreated beta-thalassaemia major, cystic fibrosis and HbSS sickle-cell disease sharply reduce viability, but outcome varies with environment and treatment. Their persistence cannot be explained by lethality alone. HbS and some thalassaemia alleles are maintained in malarial regions because heterozygotes receive protection against severe Plasmodium falciparum malaria—balanced polymorphism, demonstrated for sickle-cell trait by A. C. Allison.

Anthropological significance

Small populations, endogamy and consanguinity can increase homozygosity of rare recessives. Pedigree analysis and population screening inform non-directive counselling, while modern treatment changes selection coefficients. Labels must not stigmatise communities or imply that carriers are diseased.